Clinical, psychological, and neuropathological investigations have shown that most individuals who develop very mild cognitive impairment (clinical dementia rating 0.5) who meet criteria for mild cognitive impairment-MCI, have Alzheimer's disease (AD). Importantly, pathological studies of elderly individuals who die when they are still cognitively normal as well as persons with Down syndrome demonstrate that the neuropathology of AD (plaques and tangles) begins many years (approximately 10-25) prior to the onset of any clinical symptoms or signs of dementia (i.e. pre-clinical AD). Since cell loss is present even at the earliest clinical stages of AD and promising treatments that can potentially delay the onset or prevent the progression of AD are on the horizon, it will be very important to have biomarkers that 1) will predict development of AD in those that are normal; 2) will be helpful in differentiating subjects with very mild impairment due to AD from those that are clinically normal; and 3) will be useful in monitoring or predicting response to specific treatments. The hypothesis of this proposal is that new biomarkers can be developed and improved that will assist in both predicting development and progression of AD as well as improving early diagnosis. We will test this hypothesis, based on our preliminary data, in the following aims: 1. To assess the ability of a high ratio of Abeta40/42 in CSF lipoproteins in cognitively normal eldedy individuals to predict progression to mild cognitive impairment (MCI) and dementia. In addition, we will determine if repeat CSF assessment of the same parameters 4-5 years after the first analysis is useful in assessing dementia dsk and progression. 2. To assess the sensitivity and specificity of the CSF sulfatide (ST)/phosphatidylinositol (PI) ratio as a biomarker for AD and test the hypotheses that 1) low CSF ST/PI ratio in cognitively normal elderly individuals predicts progression to very mild dementia (MCI) and 2) low CSF ST/PI ratio predicts progression from very mild dementia (MCI) to mild dementia. 3. To determine whether other established AD biomarkers (e.g. Abeta42, tau, p-tau231) alone or in combination with the CSF Abeta40/42 ratio in lipoproteins and the ST/PI ratio best predicts progression of cognitive change. We will also begin to assess possible AD biomarkers in middle-aged adults (ages 45-60) who are children of parents with or without AD.